The present invention relates to a novel selective activated blood coagulation factor X (hereinafter referred to as [FXa]) inhibitor represented by the general formula (1).
The anticoagulant therapy plays an important role for thromboembolic diseases such as cardiac infarction, cerebral thrombosis, peripheral arterial thrombosis, and deep venous thrombosis as a medical treating preventing method.
Especially for preventing chronic thrombosis, a safe and suitable oral anticoagulant capable of being administered for a long period is needed. However, potassium warfarin, which is difficult to control its anticoagulation ability, is only available now, and a more easily usable anticoagulant has therefore been demanded.
Antithrombin agents have been developed as anticoagulants, but it has been known that the agents have a risk of causing hemorrhagic diathesis as a side effect, for example, on hirudine. It has been clarified that the inhibition of FXa placed in the upstream of thrombin is systematically more effective than the inhibition of the thrombin on a blood coagulation cascade, and it has further been clarified that FXa inhibitors are clinically preferable because of being weak in the side effect.
Biphenylamidine compounds expressing FXa-inhibiting activities are described in The 17th Symposium on Medicinal Chemistry, The 6th Annual Meeting of Division of Medicinal Chemistry, Abstracts, 184-185, 1997. The compounds of the present invention are novel compounds which are structurally clearly different from the biphenylamidine compounds at a point that a heteroatom is used to link a biphenylamidine structure which may interact with a S1 pocket, to a cyclic structure which may interact with an aryl-binding site.
And, cyclic imino derivatives (Japanese Unexamined Patent Publication (Kokai) Number 4-264068) disclose biphenylamidine derivatives, but the present invention is clearly different at a point that a heteroatom is bonded to the benzyl position.
Accordingly, the object of the present invention is to provide a novel compound which can be used as a clinically applicable FXa inhibitor.
The inventors of the present invention have extensively and intensively studied for achieving the above-mentioned object, and the following 1 to 10 have consequently been found out and led to the completion of the present invention.
1. A biphenylamidine derivative represented by the general formula (1), or a pharmaceutically acceptable salt thereof: 
[wherein, A represents an amidino group; R1 represents a hydrogen atom, a hydroxyl group, an amino group, a nitro group, a C1-C8 alkyl group, or a C1-C8 alkoxy group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, a C1-C8 alkoxycarbonyl group, or a hydrogen atom (provided that Y is limited to a case represented by the below-mentioned formula (1-4) when X represents the hydrogen atom); Y represents a group of the following formula (1-1): 
(wherein, n represents 0 or 1; Z represents Cxe2x80x94H or a nitrogen atom; R2 represents a hydrogen atom, an amino group, an amino C1-C4 alkyl group, a C1-C4 alkylamino group, or a di-C1-C4 alkylamino group; R3 represents a hydrogen atom or a C1-C4 alkyl group; R4 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxide group, or a hydroxy C1-C4 alkyl group), or a group of the following formula (1-2): 
[wherein, k and m each represents an integer of from 0 to 2, provided that k+mxe2x89xa72; R5 represents a hydrogen atom, an amidino group, or a group of the following formula (1-3): 
(wherein, R6 represents a C1-C4 alkyl group, an aralkyl group, or a phenyl group)], or a group of the following formula (1-4): 
(wherein, the wavy line represents an E isomer, a Z isomer, or their mixture on the basis of the double bond in an arbitrary ratio; R7 represents a hydrogen atom or a trifluoroacetyl group)].
2. The above-mentioned biphenylamidine derivative represented by the general formula (2) or a pharmaceutically acceptable salt thereof: 
[wherein, A represents an amidino group; R1 represents a hydrogen atom, a hydroxyl group, or a C1-C4 alkoxy group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, a C1-C8 alkoxycarbonyl group, or a hydrogen atom, (provided that Y is limited to a case represented by the below-mentioned formula (2-4) when X represents the hydrogen atom); Y represents a group of the following formula (2-1): 
(wherein, n represents 0 or 1; Z represents Cxe2x80x94H or a nitrogen atom; R2 represents a hydrogen atom, an amino group, an amino C1-C4 alkyl group, a methylamino group, or a dimethylamino group; R3 represents a hydrogen atom or a C1-C4 alkyl group; R4 represents a hydrogen atom, a chlorine atom, a hydroxyl group, a hydroxymethyl group, or a hydroxyethyl group), or a group of the following formula (2-2): 
[wherein, k and m each represents an integer of from 0 to 2, (provided that k+m=2); R5 is a hydrogen atom or a group of the following formula (2-3): 
(wherein, R6 represents a C1-C4 alkyl group)], or a group of the following formula (2-4): 
(wherein, the wavy line represents an E isomer, a Z isomer, or their mixture on the basis of the double bond in an arbitrary ratio; R7 represents a hydrogen atom or a trifluoroacetyl group)].
3. The above-mentioned biphenylamidine derivative represented by the general formula (3) or a pharmaceutically acceptable salt thereof: 
(wherein, A represents an amidino group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, or a C1-C8 alkoxycarbonyl group; Z represents Cxe2x80x94H or a nitrogen atom; R2 represents a hydrogen atom, an amino group, an aminomethyl group, an aminoethyl group, a methylamino group, or a dimethylamino group; R3 represents a hydrogen atom or a C1-C4 alkyl group; R4 represents a hydrogen atom, a chlorine atom, a hydroxyl group, a hydroxymethyl group, or a hydroxyethyl group).
4. The above-mentioned biphenylamidine derivative represented by the general formula (4) or a pharmaceutically acceptable salt thereof: 
(wherein, A represents an amidino group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, or a C1-C8 alkoxycarbonyl group; R8 represents a hydrogen atom, an amino group, an aminomethyl group, an aminoethyl group, or a C1-C4 alkyl group).
5. The above-mentioned biphenylamidine derivative represented by the general formula (5) or a pharmaceutically acceptable salt thereof: 
(wherein, A represents an amidino group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, or a C1-C8 alkoxycarbonyl group; R5 represents a hydrogen atom or an acetimidoyl group).
6. The above-mentioned biphenylamidine derivative represented by the general formula (6) or a pharmaceutically acceptable salt thereof. 
(wherein, the dashed line represents an E isomer, a Z isomer, or their mixture on the basis of the double bond in an arbitrary ratio; A represents an amidino group; X represents a carboxyl group, an aralkoxycarbonyl group, an aryloxycarbonyl group, a C1-C8 alkoxycarbonyl group, or a hydrogen atom; R7 represents a hydrogen atom or a trifluoroacetyl group).
7. A prodrug compound which produces the mentioned biphenylamidine derivative or a pharmaceutically acceptable salt thereof, in vivo.
8. An anticoagulant inhibitor which comprises at least the above-mentioned biphenylamidine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. A thrombus or embolus-preventing agent which comprises at least the above-mentioned biphenylamidine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
10. A thrombus or embolus-treating agent which comprises at least the above-mentioned biphenylamidine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The present invention is in detail disclosed below.
In the above-mentioned definition for the substituents of the compound of the general formula (1) according to the present invention.
The term xe2x80x9cC1-C4 alkyl groupxe2x80x9d means a linear or branched carbon chain having one to four carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, or tert-butyl group, preferably the group having one to three carbon atoms, particularly preferably methyl group or ethyl group.
The term xe2x80x9cC1-C8 alkyl groupxe2x80x9d means a linear, branched or cyclic carbon chain having one to eight carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, neopentyl group, isopentyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1, 1-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, isoheptyl group, octyl group, isooctyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or the like, preferably the group having one to four carbon atoms, particularly preferably methyl group or ethyl group.
The term xe2x80x9cC1-C8 alkoxy groupxe2x80x9d means, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, neopentyloxy group, tert-pentyloxy group, 2-methylbutoxy group, hexyloxy group, isohexyloxy group, heptyloxy group, isoheptyloxy group, octyloxy group, isooctyloxy group, or the like, preferably the group having one to four carbon atoms, most preferably methoxy group or ethoxy group.
The term xe2x80x9caralkoxycarbonyl groupxe2x80x9d bonded to the benzene ring as X means benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 3-trifluoromethylbenzyloxycarbonyl group, 3-oxohydroisobenzofuranyloxycarbonyl group, or the like, preferably benzyloxycarbonyl group or 3-oxohydroisobenzofuranyloxycarbonyl group.
The term xe2x80x9caryloxycarbonyl groupxe2x80x9d means phenoxycarbonyl group, naphthyloxycarbonyl group, 4-methylphenoxycarbonyl group, 3-chlorophenoxycarbonyl group, 4-methoxyphenylcarbonyl group, indan-5-yloxycarbonyl group, or the like, preferably phenoxycarbonyl group or indan-5-yloxycarbonyl group.
The term xe2x80x9cC1-C8 alkoxycarbonyl groupxe2x80x9d means methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group, or methoxycarbonyl group which is substituted by an acetoxy group, a pivaloyloxy group or a 5-methyl-3-oxo-2,4-dioxolenyl group, or the like, preferably methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, acetoxymethyloxycarbonyl group, pivaloyloxymethyloxycarbonyl group, (5-methyl-3-oxo-2,4-dioxonyl)methyloxycarbonyl group, or ethoxycarbonyloxyethoxycarbonyl group.
The term xe2x80x9camino C1-C4 alkyl groupxe2x80x9d means amino methyl group, 1-aminoethyl group, 2-aminoethyl group, 1-aminopropyl group, 2-aminopropyl group, 3-aminopropyl group, 1-aminomethylethyl group, 1-aminobutyl group, 4-aminobutyl group, or the like, preferably aminomethyl group, 1-aminoethyl group or 2-aminoethyl group, more preferably aminomethyl group or 2-aminoethyl group.
The term xe2x80x9cC1-C4 alkylamino groupxe2x80x9d means methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, or the like, preferably methylamino group, ethylamino group or propylamino group, more preferably methylamino group.
The term xe2x80x9cdi-C1-C4 alkylamino groupxe2x80x9d means dimethylamino group, methylethylamino group, methylisopropylamino group, diethylamino group, diisopropylamino group, dibutylamino group, or the like, preferably dimethylamino group.
The term xe2x80x9chydroxy C1-C4 alkyl groupxe2x80x9d means hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxymethylethyl group, 1-hydroxybutyl group, 4-hydroxybutyl group, or the like, preferably hydroxymethyl group, 1-hydroxyethyl group or 2-hydroxyethyl group, more preferably hydroxymethyl group, or 2-hydroxyethyl group.
The compound (1) of the present invention forms acid addition salts in some cases, while the compound (1) forms salts with bases in dependence on the kinds of the substituents in other cases. Such the salts are particularly not limited, when the salts are pharmaceutically acceptable salts, and specifically include mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, and sulfate; organic sulfonates such as methane sulfonate, 2-hydroxyethanesulfonate, and p-toluenesulfonate; and organic carboxylates such as acetate, trifluoroacetate, propionate, oxalate, malonate, succinate, glutarate, adipate, tartarate, maleate, malate, and mandelate as acid addition salts, and further include salts with inorganic bases, such as sodium salt, potassium salt, magnesium salt, calcium salt, and aluminum salt, and salts with organic bases, such as methylamine salt, ethylamine salt, lysine salt, and ornithine salt, as base addition salts.
The preferable compounds of the present invention are shown in the table 1.
The more preferable compounds are the compounds having the following compound numbers among the compounds shown in the table 1. 1, 8, 10, 18, 30, 32, 83, 88, 90, 92, 96, 97, 100, 108, 110, 111, 112, 113, 114,122, 123,173,174.
A typical method for synthesizing the compound represented by the general formula (1) according to the present invention is explained below.
The present compound represented by the general formula (1), wherein X1 represents a C1-C4 alkoxycarbonyl group or a hydrogen atom, can fundamentally be synthesized according to the following reaction formula. 
(wherein A, R1, and Y mean the same substituents as the substituents defined in the above-mentioned general formula (1), respectively; X1 means a C1-C4 alkoxycarbonyl group or a hydrogen atom; and R8 means a C1-C4 alkyl group).
Namely, the etherification reaction and the amidination reaction shown in the above-mentioned scheme 1 are carried out by converting the hydroxymethylphenylbenzonitrile compound into the alkoxymethylphenylbenzonitrile compound, for example, by a method shown in the below (i) or (ii), and subsequently applying a subsequently shown treatment (iii) or (iv) to the obtained alkoxymethylphenylbenzonitrile compound. The biphenylamidine derivative which is the compound of the present invention is thus obtained.
(i) The etherification reaction in the presence of a phosphine and an azodicarboxylic acid derivative: the etherification reaction of the hydroxymethylphenylbenzonitrile compound with an alcohol (YOH) is carried out, for example, by a method described in O. Mitsunobu, Synthesis, 1 (1981).
Usually, the reaction proceeds by dissolving the hydroxymethylphenylbenzonitrile compound, which may, if necessary, be protected, in an anhydrous aprotic solvent such as benzene, toluene, THF or an aliphatic ether, adding the alcohol (YOH) to the solution, adding a trialkylphosphine or a triarylphosphine with stirring, and then further adding an azodicarboxylic acid derivative such as diethyl azodicarboxylate (DEAD) or azodicarboxylic acid bisdimethylamide (TMAD). The reaction is usually carried out using tributylphosphine or triphenylphosphine as the phosphine at 0-80xc2x0 C. for 6-24 hours, preferably at 20-50xc2x0 C. for 8-16 hours.
(ii) The etherification reaction through a trichloroacetimidate: the etherification reaction of the hydroxymethylphenylbenzonitrile compound (1) with the alcohol (YOH) may be carried out by converting the hydroxymethylphenylbenzonitrile compound, which is protected, if necessary, into the trichloroacetimidate and then reacting the trichloroacetimidate with the alcohol (YOH).
The trichloroacetimidate is obtained by dropwisely adding trichloroacetonitrile to the solution of an alkoxide obtained from the hydroxymethylphenylbenzonitrile compound and a metal hydride such as sodium hydride in an etherial anhydrous solvent in the atmosphere of nitrogen, stirring the mixture for 1-5 hours, adding the solvent mixture of a lower alcohol with a hydrocarbon solvent such as pentane, hexane or heptane, stirring the mixture, filtering off insolubles and then concentrating the filtrate. The alkoxide is usually prepared in THF or diethyl ether at xe2x88x9278 to +30xc2x0 C., and the reaction of the alkoxide with the trichloroacetonitrile proceeds by stirring at 0-50xc2x0 C. for 1-12 hours. The reaction is preferably carried out by preparing the alkoxide at xe2x88x9230 to +10xc2x0 C., dropwisely adding the trichloroacetonitrile and then stirring the reaction solution at 10-40xc2x0 C. for 2-6 hours.
The alkoxymethylphenylbenzonitrile compound can be synthesized by mixing the obtained trichloroacetimidate with the alcohol (YOH) in the presence of an organic acid such as a sulfonic acid in an aliphatic ether such as diethyl ether or THF and then stirring the mixture at xe2x88x9220 to 40xc2x0 C. for 6-24 hours. The reaction is carried out by using p-toluene sulfonic acid or trifluoromethane sulfonic acid as the organic acid, starting the reaction at xe2x88x9220 to 0xc2x0 C., gradually raising the temperature of the reaction solution up to 10-30xc2x0 C. and simultaneously stirring the reaction solution for 12 to 18 hours.
(iii) The biphenylamidine derivative represented by the general formula (1), wherein X1 is a hydrogen atom, can be synthesized by reacting the alkoxymethylphenylbenzonitrile compound with ammonium chloride in the presence of a trialkylaluminum.
The reaction usually proceeds by mixing the ammonium chloride with the trialkylaluminum, such as trimethylaluminum, triethylaluminum or tributylaluminum, dissolved in an anhydrous hydrocarbon solvent such as pentane or hexane in an anhydrous hydrocarbon solvent such as hexane, benzene or toluene at xe2x88x9210 to 50xc2x0 C., stirring the mixture for 1-12 hours, adding the alkoxymethylphenylbenzonitrile compound to the mixture at xe2x88x9230 to +30xc2x0 C. and stirring at 10-100xc2x0 C. for 6-24 hours. The reaction is preferably carried out by adding the ammonium chloride to benzene or toluene, dropwisely adding the pentane or hexane solution of the trimethylaluminum to the mixture at 0 to +30xc2x0 C., stirring for 2 to 6 hour, adding the benzene or toluene solution of the alkoxymethylphenylbenzonitrile compound and further stirring at 40 to 80xc2x0 C. for 12 to 18 hours.
(iv) The biphenylamidine derivative represented by the general formula (1), wherein X1 represents a hydrogen atom or a C1-C4 alkoxycarbonyl group, can be produced by reacting ammonia or one of various kinds of amines with the imidate (5) obtained by reacting the nitrile compound with a C1-C4 alcohol (R8OH) containing hydrogen chloride. For example, the biphenylamidine derivative can be synthesized by the method mentioned in the following (iv-a) or (iv-b).
(iv-a) The amidination reaction through an imidation reaction using the alcohol solution of a hydrogen halide: the reaction for obtaining the imidate from the alkoxymethylphenylbenzonitrile and the alcohol (R8OH) proceeds, for example, by dissolving the alkoxymethylphenylbenzonitrile compound in the C1-C4 alcohol (R8OH) containing a hydrogen halide such as hydrogen chloride or hydrogen bromide and stirring the mixture. The reaction is usually carried out at xe2x88x9220 to 30xc2x0 C. for 12 to 96 hours. The reaction is preferably carried out at xe2x88x9210 to +30xc2x0 C. for 24 to 72 hours.
The reaction of the imidate with the ammonia proceeds by stirring the imidate in a C1-C4 alcohol, such as methanol or ethanol, an aliphatic ether, such as diethyl ether, a halogenated hydrocarbon, such as dichloromethane or chloroform, or their mixture solvent which contains the ammonia or an amine, such as hydroxylamine, hydrazine or a carbamate ester, to produce the biphenylamidine derivative which is the compound of the present invention. The reaction is usually carried out at xe2x88x9210 to +50xc2x0 C. for 1 to 48 hours. The reaction is preferably carried out at 0 to +30xc2x0 C. for 2 to 12 hours.
(iv-b) The amidination reaction through the imidate prepared, while directly bubbling a hydrogen halide into the reaction solution: the reaction of the alkoxymethylphenylbenzonitrile compound with the alcohol (R8OH) proceeds, for example, by dissolving the alkoxymethylphenylbenzonitrile compound in an aliphatic ether such as diethyl ether, a halogenated hydrocarbon such as chloroform, or an aprotic olvent such as benzene, adding an equivalent or excessive amount of the C1-C4 alcohol (R8OH), blowing a hydrogen halide such as hydrogen chloride or hydrogen bromide in the mixture at xe2x88x9230 to 0xc2x0 C. for 30 minutes to 6 hours with stirring, stopping the bubbling of the hydrogen halide, and further stirring at 0-50xc2x0 C. for 3-96 hours. The reaction is preferably carried out by bubbling the hydrogen chloride in the halogenated hydrocarbon containing an equivalent or excessive amount of methanol or ethanol at xe2x88x9210 to 0xc2x0 C. for 1-3 hours with stirring, stopping the bubbling of the hydrochloride, and further stirring at 10-40xc2x0 C. for 8-24 hours.
The imidate thus obtained is stirred in a C1-C4 alcohol solvent, such as methanol or ethanol, an aliphatic ether solvent, such as diethyl ether, a halogenated hydrocarbon solvent, such as chloroform, or their mixture solvent which contains ammonia or an amine, such as hydroxylamine, hydrazine or a carbamate ester, thereby capable of being converted into the biphenylamidine derivative which is the compound of the invention. The reaction is usually carried out at xe2x88x9220 to 50xc2x0 C. for 1 to 48 hours. The reaction is preferably carried out in saturated ammonia ethanol at xe2x88x920 to +30xc2x0 C. for 2 to 12 hours.
The compound represented by the general formula (1), wherein X represents a carboxyl group, is produced by hydrolyzing the ester group of the compound having the C1-C4 alkoxycarbonyl group as X, among the biphenylamidine produced according to the above-mentioned (iv). 
[wherein, A, R1, and Y mean the same substituents as the substituents defined in the above-mentioned general formula (1), respectively ; R9 represents a C1-C4 alkyl group].
Namely, the hydrolysis reaction represented by the above-mentioned scheme 2 may, if necessary, be carried out under a basic condition, an acidic condition or a neutral condition. A base used in the reaction under the basic condition includes sodium hydroxidde, potassium hydroxide, lithium hydroxide and barium hydroxide, and an acid used in the reaction under the acidic condition includes hydrochloric acid, sulfuric acid, Lewis acids such as boron trifluoride, trifluoromethane sulfonic acid and p-toluene sulfonic acid. A substance used in the reaction under the neutral condition includes the alkali metal salts of halide ions, thiol and selenol, such as lithium iodide and lithium bromide, trimethylsilane iodide, and enzymes such as esterases. A solvent used in the reaction includes polar solvents such as water, alcohols, acetone, dioxane, THF, DMF, and DMSO, and their mixtures. The reaction is usually carried out at room temperature or under heating for 2-96 hours. Suitable conditions such as a suitable reaction temperature and a suitable reaction time depend on reaction conditions used in the reaction, and are suitably selected by a conventional method.
And, the compound represented by the general formula (1), wherein R5 represents a hydrogen atom, synthesized by the above-mentioned methods may be reacted with an imidate compound in the presence of a base in a proper solvent to introduce an alkanoylimidoyl group, an arylalkanoylimidoyl group or a benzoylimidoyl group. 
[wherein, A, R1, R6, k, and, m mean the same substituents as the substituents defined in the general formula (1), respectively].
Namely, the imidoylation reaction represented by the above-mentioned scheme 3 proceeds mixing the compound having the secondary amino group with a suitable imidate compound in the presence of a base in water, a C1-C4 alcohol, such as methanol or ethanol, an aliphatic ether, such as diethyl ether, a halogenated hydrocarbon, such as chloroform, a polar solvent, such as DMF or DMSO, or their mixture solvent with stirring. The reaction is usually carried out at room temperature for 1 to 24 hours. The base herein used includes N-methylmorpholine, triethylamine, diisopropylethylamine, sodium hydroxide and potassium hydroxide.
The carboxyl group of the compound of the general formula (1), wherein the substituent X represents the carboxyl group, may be converted into various kinds of ester groups by the following methods (viii), (ix), and (x).
(viii) The conversion of the carboxyl group into an alkoxycarbonyl group: the compound of the formula (1), wherein the substituent X represents the carboxyl group, is reacted with an equivalent or excessive amount of an alkylating agent (for example, an acyloxymethyl chloride such as acetoxymethyl chloride or pivaloyloxymethyl chloride, an allyl chloride compound, or a benzyl chloride compound) in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a halogenated hydrocarbon such as dichloromethane, an aliphatic ether such as THF, an aprotic polar solvent such as DMF, or their mixture solvent, at xe2x88x9210 to +80xc2x0 C., whereby the carboxyl group can be converted into the alkoxycarbonyl group. The conversion reaction is preferably carried out using an equivalent or slightly excessive amount of the alkylating agent in the presence of diisopropylethylamine at 20-60xc2x0 C. for 2-24 hours.
(ix) The conversion of the carboxyl group into an aralkoxycarbonyl group: the compound represented by the general formula (1), wherein the substituent X represents the carboxyl group, is reacted with an equivalent or excessive amount of an alcohol such as benzyl alcohol in the presence of an acid catalyst such as hydrogen chloride, sulfuric acid or a sulfonic acid in a halogenated hydrocarbon such as dichloromethane as a solvent, whereby the carboxyl group can be converted into the aralkoxycarbonyl group. The reaction is usually carried out at room temperature or under heating for 1-72 hours. The reaction is preferably carried out using an equivalent or slightly excessive amount of the alcohol in the presence of diisopropylethylamine at 20 to 60xc2x0 C. for 2 to 24 hours.
(x) The conversion of the carboxyl group into an aryloxycarbonyl group: the compound represented by the formula (1), wherein the substituent X represents the carboxyl group, is reacted with an equivalent or excessive amount of an aromatic compound having a hydroxyl group, such as phenol, in the presence of a condensing agent such as dicyclohexylcarbodiimide in an aliphatic ether such as diethyl ether as a solvent, whereby the carboxyl group can be converted into the aryloxycarbonyl group. The reaction is usually carried out at 0 to 50xc2x0 C. for 1-48 hours. The reaction is preferably carried out at room temperature for 3-24 hours.
Further, the compound represented by the general formula (1) can be produced by arbitrarily combining processes capable of being adopted by those skilled in the art, such as other known etherification, amidination, hydrolysis, and alkylimidoylation processes.
The above produced biphenylamidine derivative represented by the general formula (1) can be isolated or purified by a known method, such as extraction, precipitation, fractional chromatography, fractional crystallization or recrystallization. The pharmaceutically acceptable salt of the compound of the present invention can be produced by the application of an ordinary salt-forming reaction.